Approaches to the synthesis of crysothame and the avermectin southern hemiphere

Steel, Katherine Isobel Mary (1986) Approaches to the synthesis of crysothame and the avermectin southern hemiphere. University of Southampton, Doctoral Thesis.

Abstract

Synthetic studies towards the hexahydrobenzofuran subunit of the avermectin and milbemycin families of antiparasitic agents are described. Peterson reaction of 4-methoxy-3-buten-2-one with phenylthiomethyl-trimethylsilane gave 4-methoxy-3-methyl-2-phenylthio-1,3-butadiene (118). This underwent Diels-Alder addition with maleic anhydride to give 6-methoxy-4-methyl-3-phenylthio-cyclohex-4-ene-1,2-dicarboxylic anhydride (119). Diels-Alder reactions with but-2-enolide (109) were attempted under a range of thermal and Lewis acid catalysed conditions but no adduct was obtained. The silicon substituted diene 4-acetoxy-2-methyl-1-trimethylsily-1,3-butadiene (85) and the benzoyl and t-butyldimethylsilyloxy analogues, (93) and (103) respectively, were prepared. The scope and limitations of such dienes in Diels-Alder reactions with variously protected 5-hydroxy-3-penten-2-ones and with ethyl 4-oxo-2-pentenoate were explored but the yields obtained were too low to be synthetically viable. A synthetic approach to the diterpenoid spiroacetal chrysothame (1) is reported. 4-Methoxymethoxy-3,4,4a,5,-6,7,8,8a-octahydro-5,5,8a-trimethyl-4α,4aα,8aβ-naphthalene -1,2-dimethanol (52) was prepared in three steps from the Diels-Alder adduct of 2-vinyl-1,6,6-trimethylcyclohexene with dimethyl acetylenedicarboxylate. Attempts to prepare a monotosylate of this diol resulted in formation of the corresponding dihydrofuran (53). 2-(1-trimethylsilyloxy-ethyl)-1,3,3-trimethylcyclohexene (61) was prepared in three steps from β-cyclocitral. Cycloadditions of this diene with olefinic and acetylenic esters were explored. No adduct was obtained, possibly because the diene exists preferentially in the transoid conformation. Preliminary investigations into a synthesis of chrysothame via conjugate addition to β-cyclocitral are described. Treatment of β-cyclocitral with diethyl aluminium cyanide or divinyl magnesium cuprate both gave a low yield of 1,4-adduct. (D72197/87)

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